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Simple Summary: Immune checkpoint inhibitors offer the chance for the durable disease control of advanced/metastatic non-small-cell lung cancer (NSCLC). However, they come with the risk of immune-related adverse events (irAEs) which may be severe or life-threatening, or lead to long-term toxicity. We confirm that the occurrence of irAEs is associated with improved survival outcomes in patients with NSCLC treated with pembrolizumab. These survival benefits are only seen in patients with particular irAEs, or mild irAEs. Significantly, we account for the time-dependent association between time on treatment and the development of irAEs. Low levels of systemic inflammation, as defined by simple biomarkers of systemic inflammation, have previously been shown to predict the occurrence of irAEs. However, we find that their predictive power is confounded by their independent prognostic value. We suggest that these findings are taken into account by other studies investigating potential biomarkers of irAE risk. Background: Pembrolizumab monotherapy for non-small-cell lung cancer (NSCLC) expressing PD-L1 ≥ 50% doubles five-year survival rates compared to chemotherapy. However, immune-related adverse events (irAEs) can cause severe, long-term toxicity necessitating high-dose steroids and/or treatment cessation. Interestingly, patients experiencing irAEs demonstrate better survival outcomes. Biomarkers of systemic inflammation, including the Scottish Inflammatory Prognostic Score (SIPS), also predict survival in this patient group. This study examines the relationship between inflammatory status, irAEs, and survival outcomes in NSCLC. Methods: A retrospective analysis was conducted on patients with NSCLC expressing PD-L1 ≥ 50% receiving first-line pembrolizumab monotherapy at a large cancer centre in Scotland. Regression analyses were conducted to examine the relationship between SIPS, irAEs, and survival. Results: 83/262 eligible patients (32%) experienced an irAE. Dermatological, endocrine, gastrointestinal, and hepatic, but not pulmonary, irAEs were associated with prolonged PFS and OS (p <= 0.011). Mild irAEs were associated with better PFS and OS in all patients, including on time-dependent analyses (HR0.61 [95% CI 0.41–0.90], p = 0.014 and HR0.41 [95% CI 0.26–0.63], p < 0.001, respectively). SIPS predicted PFS (HR 1.60 [95% CI 1.34–1.90], p < 0.001) and OS (HR 1.69 [95% CI 1.41–2.02], p < 0.001). SIPS predicted the occurrence of any irAE in all patients (p = 0.011), but not on 24-week landmark analyses (p = 0.174). The occurrence of irAEs predicted favourable outcomes regardless of the baseline inflammatory status (p = 0.015). Conclusion: The occurrence of certain irAEs is associated with a survival benefit in patients with NSCLC expressing PD-L1 ≥ 50% receiving pembrolizumab. We find that the association between low levels of systemic inflammation and the risk of irAEs is confounded by their independent prognostic value. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgery or conventional radical radiotherapy are established curative treatment options for patients with localised, stage I non-small-cell lung cancer (NSCLC). Another option, stereotactic ablative body radiotherapy (SABR), has emerged over the last decade. We sought to understand the impact of the introduction of SABR at our institute by investigating outcomes in 1143 patients diagnosed with stage I NSCLC between 2012–2019. We find that clinical factors such as age, fitness and the presence of other significant health problems (i.e., comorbidities) correlated with treatment choice. For example, younger, fitter and less comorbid patients were more likely to be treated with surgery. Similar to other studies in this area, we find that the introduction of SABR improved survival outcomes of patients with stage I NSCLC. The greatest improvement was seen in patients treated with surgery. We suggest this is because the availability of SABR as a safe and effective alternative treatment improved the selection of patients for surgical treatment. These findings are important as they may help clinicians and patients chose the most appropriate treatment option. Introduction: Stereotactic ablative body radiotherapy (SABR) offers patients with stage I non-small-cell lung cancer (NSCLC) a safe, effective radical therapy option. The impact of introducing SABR at a Scottish regional cancer centre was studied. Methods: The Edinburgh Cancer Centre Lung Cancer Database was assessed. Treatment patterns and outcomes were compared across treatment groups (no radical therapy (NRT), conventional radical radiotherapy (CRRT), SABR and surgery) and across three time periods reflecting the availability of SABR (A, January 2012/2013 (pre-SABR); B, 2014/2016 (introduction of SABR); C, 2017/2019, (SABR established)). Results: 1143 patients with stage I NSCLC were identified. Treatment was NRT in 361 (32%), CRRT in 182 (16%), SABR in 132 (12%) and surgery in 468 (41%) patients. Age, performance status, and comorbidities correlated with treatment choice. The median survival increased from 32.5 months in time period A to 38.8 months in period B to 48.8 months in time period C. The greatest improvement in survival was seen in patients treated with surgery between time periods A and C (HR 0.69 (95% CI 0.56–0.86), p < 0.001). The proportion of patients receiving a radical therapy rose between time periods A and C in younger (age ≤ 65, 65–74 and 75–84 years), fitter (PS 0 and 1), and less comorbid patients (CCI 0 and 1–2), but fell in other patient groups. Conclusions: The introduction and establishment of SABR for stage I NSCLC has improved survival outcomes in Southeast Scotland. Increasing SABR utilisation appears to have enhanced the selection of surgical patients and increased the proportion of patients receiving a radical therapy. [ABSTRACT FROM AUTHOR]